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Title:The role of AUTS2 in neurodevelopment and neurological disease
Author(s):Weisner, Patricia Anne
Director of Research:Stubbs, Lisa J
Doctoral Committee Chair(s):Stubbs, Lisa J
Doctoral Committee Member(s):Ceman, Stephanie; Raetzman, Lori; Chung, Hee Jung
Department / Program:School of Molecular & Cell Bio
Degree Granting Institution:University of Illinois at Urbana-Champaign
Subject(s):Autism Susceptibility Candidate 2 (Auts2)
Abstract:The Autism Susceptibility Candidate 2 (AUTS2) gene is a critical neuronal gene that is involved in several related developmental pathways, including regulation of neurite outgrowth and neuronal migration, and transcriptional activation of neuronally active genes. Disruption of AUTS2 has been implicated in a wide variety of neurological and neurodevelopmental disorders, including autism, epilepsy, cognitive impairment, and Attention Deficit Hyperactive Disorder (ADHD). Additionally, single nucleotide polymorphisms (SNPs) in the AUTS2 locus are associated with psychiatric disorders, including schizophrenia, bipolar disorder, and depression, as well as addiction-related behaviors and dyslexia. In order to better understand the connections between AUTS2 and neurological disease, we utilized a reciprocal translocation mutation, called 16Gso, which disrupts mouse chromosome 5 around 60kb downstream of the Auts2 locus and results in the down-regulation of the full- length Auts2 isoform in adult mouse brain. 16Gso animals display a suite of behaviors that closely mimic those seen in humans with AUTS2 mutations, as well as those found in AUTS2- related syndromes, including craniofacial abnormalities, seizures, repetitive behaviors, and changes in alcohol preference. In addition, 16Gso mutants show reduced activity, as well as an inability to regulate movement in stressful novel environments such as the elevated plus maze, but have normal patterns of movement in their home environment, suggesting movement abnormalities are triggered by stress or novelty. In addition, 16Gso mutants show cellular defects in the hippocampal dentate gyrus and cerebellar Purkinje cells, two cell populations with pathological changes in a number of AUTS2- related neurological conditions. Specifically, 16Gso animals have reduced numbers of Purkinje cells, and remaining cells have abnormal dendrites and are abnormally aligned. In the dentate gyrus, granule cells no longer express Auts2, and remaining cells have abnormal dendritic projections and fail to express markers of maturity. Our evidence suggests that without proper Auts2 expression, cells in the cerebellum and hippocampus retain an immature phenotype and fail to develop normal neurites. These studies present the first evidence connecting cellular phenotypes in Auts2-deficient animals to phenotypes that parallel those seen in humans with AUTS2 mutations. The AUTS2 gene is large, with several alternative promoters and splicing variants, and sequence analysis suggests the different gene isoforms may have varying functions in the brain. Based on this information, as well as functional studies implicating the cytoplasmic mouse Auts2 protein in neurite regulation pathways, we hypothesized that the various Auts2 isoforms may be differentially expressed in neurodevelopment and neurodifferentiation. To test this hypothesis, we conducted a full expression profile of the dominant Auts2 isoforms in the developing mouse brain. We identified varying tissue- and time point-specific expression patterns among the isoforms, with significant differences in level of expression, regional and subcellular localization. These data suggest that the Auts2 isoforms are differentially regulated during neurodevelopment, and that the full-length isoform carries particular importance in late developmental processes and adult brain function. The studies presented here offer the first comprehensive expression analysis of the individual Auts2 isoforms, as well as the opportunity to connect Auts2 dysregulation to region- specific neuronal phenotypes in an animal model that mimics AUTS2-associated behaviors. Our data advance the understanding of the nuances of Auts2 isoform expression, and provide a model to better understand the role of Auts2 in neuronal disease.
Issue Date:2015-07-28
Rights Information:Copyright 2015 Patricia Weisner
Date Available in IDEALS:2016-03-02
Date Deposited:2015-12

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